In 2012, B cell-malignancies constituted approximately 5% of newly diagnosed cancers in the US. Age-adjusted incidence rates for acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell non-Hodgkin lymphoma (B-NHL) were 1.6, 4.2, and 16.5 per 100,000 men and women per year, respectively (Howlader N, Noone A M, Krapcho M, Neyman N, Aminou R, Altekruse S F, Kosary C L, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner M P, Lewis D R, Chen H S, Feuer E J, Cronin K A (eds). SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, Md., http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, 2012). Despite repeated intensive standard treatments B cell-malignancies may become refractory to or relapse after therapy and frequently remain incurable. Therefore, a high medical need exists for innovative treatment modalities to improve the outcome in these patient populations.
Antibody-based cancer therapies require a target antigen firmly bound to the surface of cancer cells in order to be active. By binding to the surface target, the antibody can directly deliver a deadly signal to the cancer cell or indirectly by, for example, recruiting a cytotoxic T cell, if it is a bispecific antibody. In an ideal treatment scenario, a target antigen is abundantly present and accessible on every cancer cell and is absent, shielded or much less abundant on normal cells. This situation provides the basis for a therapeutic window in which a defined amount of the antibody-based therapeutic effectively hits cancer cells but spares normal cells.
Monoclonal antibodies were first added to standard chemotherapy about 20 years ago, yet this combination has not proved to be completely curative in B cell-malignancies. In recent years, a novel therapeutic approach with bispecific single-chain antibodies has entered clinical studies and shown promising initial results. Multispecific antibodies, such as bispecific antibodies, which re-direct T-cells, are of special interest for the treatment of cancer target cells. Re-directing of T cells comprises that T cells are equipped with an antigen receptor specificity which differs from the T cells' clonotypic natural antigen receptor specificity, i.e. the re-directed T-cells comprise for example a binding domain recognizing said cancer target cells. This can e.g. be achieved by T cell engaging bi- or multi-functional antibodies or antibody derivatives, such as bispecific antibodies comprising inter alia a CD3-specific binding domain, or by transduction of T cells with chimeric antigen receptors (CARs) such as CARs recognizing CD19 (see Knochenderfer et al., Nature Reviews 2013; Clinical Oncology; “Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors”). Bispecific antibodies targeting CD19 or CD20 on B cells and CD3 on T cells are of special interest for the treatment of B cell-malignancies. Blinatumomab (sometimes also denoted as AMG 103 or MT103) is a recombinant CD19×CD3 bispecific scFv antibody consisting of four immunoglobulin variable domains assembled into a single polypeptide chain. Two of the variable domains form the binding site for CD19 which is a cell surface antigen expressed on most normal and malignant B cells. The other two variable domains form the binding site for CD3 which is part of the T cell-receptor complex on T cells. By binding to CD19 on a normal or malignant B cell and concomitantly engaging a T cell via CD3, Blinatumomab induces the formation of a cytolytic synapse (Offner et al. Mol. Immunol. 2006; 43:763-71), thereby leading to the eradication of the bound B cell. Blinatumomab is designed to polyclonally redirect the body's cytotoxic T cells against multiple B tumor cells.
Various clinical studies evaluating the safety and efficacy of Blinatumomab have been conducted both in B-NHL (Bargou et al. Science. 2008; 321:974-7) and B-precursor ALL (Topp et al. J Clin Oncol. 2011; 29:2493-8). These studies established clinical proof of concept for the high therapeutic potential of the bispecific single-chain antibody format in general and of Blinatumomab in special and validated its further development in B-NHL, ALL and CLL.
Though antibodies are an effective means in treating many disorders, in particular cancer, their administration is not necessarily devoid of side effects. A “side effect” which is sometimes also denoted as “adverse effect” or more frequently as “adverse event” (sometimes also denoted as “AE”) in clinical studies, is a harmful and undesired effect resulting from medication in the treatment of a patient with a re-directed T-cell for example by way of a multispecific antibody or more preferably a bispecific antibody comprising a CD3-specific binding domain. Adverse effects may cause a reversible or irreversible change in the health status of a patient. As adverse effects could be harmful and potentially even life-threatening it is highly desirable to avoid them.
However, it is difficult to design a therapy which comprises re-directing of T-cells against target cells in a patient (for example a CD19×CD3 bispecific single-chain antibody-based therapy) which does not cause neurological symptoms, or to put it differently, it is desired to provide such a therapy, for example a CD19×CD3 bispecific single-chain antibody-based therapy with increased patient tolerability, i.e. reduced or even no harmful side effects such as CNS AEs. It is particularly desired to mitigate CNS AEs to an extent avoiding discontinuation of treatment due to CNS AEs thus allowing the patients to fully benefit from the treatment.
There is thus a strong need in the art to provide means and methods which attenuate or even avoid the above mentioned side effects that typically accompany a therapy that is based on re-directed T-cells (such as a therapy that makes use of a CD19×CD3 bispecific single-chain antibody).
The present invention addresses this need and thus provides, as a solution to the technical problem, a compound which decreases or inhibits the binding of mammalian T-cells to mammalian endothelial cells for use in a method of prophylaxis and/or amelioration and/or treatment of clinical adverse events caused by therapy which comprises re-directing of T-cells against target cells in a patient.
Further embodiments of the present invention are characterized and described herein and also reflected in the claims.